Study Reveals Anti-Stress, Anxiety, Inflammation Meds Reduce Post-Surgical Metastasis

Shamgar Ben-Eliayahu, PhD, Tel Aviv University, is an ICRF Project Grant recipient who is currently conducting clinical trials on colorectal rectal patients being treated with a beta-blocker, anxiolytic, and pain drugs alongside tumor removal to prevent metastasis.

In honor of Colon Cancer Awareness Month, can you describe your research on the impact of stress, inflammatory responses and physiological trauma on immunity and on cancer metastasis?  

Surgery is imperative to the treatment of most types of cancer and usually succeeds in removing the primary tumor (e.g., breast or colorectal tumors). However, many patients that undergo a successful surgery will unfortunately develop a metastatic disease (e.g., 35 percent of colorectal cancer patients) and will often die from it (80 percent of colorectal cancer patients with metastases). Having cancer, awaiting surgery, surgery itself, and the post-operative pain and recovery period, all produce anxiety, stress, and inflammatory responses. We and others have shown that these responses constitute risk factors for promotion of pre-existing micro-metastases and initiation of new metastases. These deleterious effects are mediated through the body release of adrenergic hormones (adrenaline and nor-adrenaline) and the pro-inflammatory factors prostaglandins. In the critical perioperative period, minor manipulations of physiological responses can exert a non-proportional impact on cancer progression. However, this critical period is traditionally not used for anti-metastatic interventions.

Can you tell us about your groundbreaking study regarding the effects of anti-stress-inflammatory meds on metastasis after tumor removal?

Given this understanding, we have developed a drug regimen based on non-patented medications which are administered during a short perioperative period. During two decades of animal studies, we showed the efficacy of this treatment in reducing post-surgical metastases and improving survival in several types of cancer*. Recently we completed two small clinical studies, treating patients with breast and colorectal cancer**. These studies have reaffirmed the safety of the treatment, and showed its benefits by reducing the tumors pro-metastatic molecular characteristics.  Most important, in 34 colorectal patients, three- and five-year follow ups indicated the recurrence was 12.5 percent in drug-treated patients (five-year follow up) and 50 percent in placebo-treated patients. A much larger study is needed to confirm this outcome and make this treatment routine in cancer patients.   The treatment has minimal-to-no adverse effects, is safe, inexpensive, and easily administered in patients (two pills twice daily, for 20 days, starting five days before surgery). The two drugs are commonly available in every pharmacy: a drug to lower blood pressure and reduce anxiety (propranolol), and a drug used to prevent pain and inflammation (etodolac). 

As an ICRF grantee, how has the organization helped to further your research? 

The long path of research that we have completed in animal studies was supported by competitive grants from the NIH/NCI (RO1 grants) and the ISF (Israel Science Foundation). However, we have now begun to launch large-scale multicenter clinical studies in colorectal and pancreatic cancer patients, which are necessary to show that the treatment can save lives of cancer patients. Consequently, our need for funding has changed and grown markedly. Usually at this stage a pharmaceutical company buys the patent, and invests a large amount of money in order to gain future profits. However, in our case, pharmaceutical companies do not have any economic incentive to do so, and we, the scientists and the physicians, have to initiate, lead, and finance these clinical studies. Some grant foundations, like the ISF, do not support clinical studies, but only basic research. Other grant foundations that do support such studies, are commonly limited in their resources compared to the pharmaceutical industry, and we are thankful for receiving such important support from ICRF, which partially covers the expenses of our ongoing clinical trials. ICRF support during the last three years also assisted us in completing our first clinical trial in colorectal cancer patients (the five-year follow up). We will need further financial assistance to continue and expand our ongoing clinical trials, and we plan to submit an additional grant application to ICRF and to other non-profit organizations.

*links: https://www.ncbi.nlm.nih.gov/pubmed/25601442 and https://www.nature.com/articles/s41568-021-00395-5
**links: https://www.ncbi.nlm.nih.gov/pubmed/28490464, and https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.32950